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Molecular and Cellular Biology, June 2004, p. 5353-5368, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5353-5368.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

FERM Domain Interaction Promotes FAK Signaling

Jill M. Dunty,1,{dagger} Veronica Gabarra-Niecko,1,{dagger} Michelle L. King,1 Derek F. J. Ceccarelli,2,3,{ddagger} Michael J. Eck,2,3 and Michael D. Schaller1,4,5,6*

Department of Cell and Developmental Biology,1 Lineberger Comprehensive Cancer,4 Comprehensive Center for Inflammatory Disorders,5 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School,2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 021153

Received 19 November 2003/ Returned for modification 5 January 2004/ Accepted 15 March 2004

From the results of deletion analyses, the FERM domain of FAK has been proposed to inhibit enzymatic activity and repress FAK signaling. We have identified a sequence in the FERM domain that is important for FAK signaling in vivo. Point mutations in this sequence had little effect upon catalytic activity in vitro. However, the mutant exhibits reduced tyrosine phosphorylation and dramatically reduced Src family kinase binding. Further, the abilities of the mutant to transduce biochemical signals and to promote cell migration were severely impaired. The results implicate a FERM domain interaction in cell adhesion-dependent activation of FAK and downstream signaling. We also show that the purified FERM domain of FAK interacts with full-length FAK in vitro, and mutation of this sequence disrupts the interaction. These findings are discussed in the context of models of FAK regulation by its FERM domain.

* Corresponding author. Mailing address: 534 Taylor Hall, CB # 7090, Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-0391. Fax: (919) 966-1856. E-mail: crispy4{at}med.unc.edu.

{dagger} J.M.D. and V.G.-N. contributed equally to this work.

{ddagger} Present address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

Molecular and Cellular Biology, June 2004, p. 5353-5368, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5353-5368.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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